In order to develop strategiesto prevent the spread of HIV-1, it is important to identify and characterize the viruses that are transmitted, particularly in high incidence areas. These analyses may illuminate the properties of the virus that determine its fitness for transmission, define the earliest target cells for virus replication, and may advance our understanding of the mechanisms of transmission. Moreover, it is likely that we can develop a better understanding of the virus-host cell interactions that influence HIV-1 pathogenesis if the clinical course of HIV-1 infection is specifically examined in relation to the virus that infects the host. Much of our current understanding of HIV-1*transmission and pathogenesis derives from studies of predominantly male cohorts in North America and Europe who are infected with subtype B HIV-1. In Africa, where the majority of HIV-1 infections and associated deaths are occurring, there.are multiple genetic subtypes of HIV-1, and subtype B is relatively uncommon. Thus, it is critical that the results of existing studies not be generalized to African populations, particularly when considering interventions to limit the spread or pathogenesis of HIV-1 infections. We have found that the majority of women in Africa are infected with a complex virus population, whereas African men and a minority of African women are infected by only a single virus variant. In contrast, previous studies of North American and European cohorts have consistently shown that only a single virus is transmitted. We hypothesize that the complex viruses that are transmitted to women in Africa may have distinct phenotypic or immunogenic properties that will influence disease progression: To address this, .we will ask whether infection that is initiated by a complex virus population will elicit a broader humoral immune response, and we will determine how the complexity of the infecting virus affects plasma and mucosal viral load and disease progression. In the course of the proposed studies, we will also determine if viral subtypes in Africa differ in their replication or pathogenic properties. We hypothesize that the viral subtype, the genetic complexity and/or the phenotype of the viral strain that infect the host will influence both systemic and mucosal virus replication, which in turn will influence progression to AIDS. The proposed combination of natural history studies and analyses of virus-host cell interactions will be focused on African women infected with non subtype B HIV-1 because this population represents approximately one third of all HIV-1 infections worldwide, yet almost nothing is known regarding HIV-1 pathogenesis in these individuals.